Bisphosphonates are chemically and enzymatically stable analogues of inorganic pyrophosphate that interfere with specific biochemical and enzymatic pathways of the bone-resorbing osteoclasts. The development of the bisphosphonates has yielded effective treatments for various diseases of excessive bone resorption, including Paget's disease of bone, myeloma, bone metastases, and osteoporosis. However, the bisphosphonates are associated with two major problems, poor oral bioavailability (<1% in humans) and a high rate of gastrointestinal mucosal damage that limit effectiveness and long-term tolerability. At TSRL, we have created carrier molecules, termed Bile Acid Conjugates (BAC) that enhance the oral bioavailability of poorly absorbed, charged molecules. The goal of the current project is to use the BAC technology to improve the oral bioavailability of alendronate, the leading bisphosphonate on the market (Fosamax). We hypothesize that the BAtify the efficacy of this therapy in an ovarectomized rodent model. This collaboration will allow us to systematically test the effect of a diverse library of BAC carrier molecules on alendronate transport, oral bioavailability, and efficacy in an animal model. [unreadable] [unreadable] Public Health Relevance: This project specifically involves the development of a new drug carrier to enhance oral absorption for poorly absorbed drugs like alendronate and other bisphosphonates currently used for the treatment of osteoporosis. 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